Working memory binding: insights from neuroimaging, behavioural and clinical studies

Working memory binding (WMB) entails the integration of multiple sources of information to form and temporarily store coherent object representations (or conjunctions). To date, cognitive research on binding has mostly focused on visual WM and change detection paradigms (i.e., the WMB task), and documented that WMB is a function sensitive and specific to Alzheimer’s Disease (AD). Following a review of the most relevant studies on the topic in Chapter I, this PhD project aimed at addressing two main pending questions: 1) Whether deficits in WMB tasks reveal abnormalities in individuals at risk of developing dementia, such as those suffering from Mild Cognitive Impairment (MCI); 2) Whether visual WMB deficits observed in AD may generalise for material processed across different modalities (i.e., crossmodal WMB). The first aim was addressed in Chapters II and III. Chapter II reports on the results from an fMRI study showing that MCI patients’ conjunctive WMB abilities are impaired compared to healthy controls, and that such WMB deficits are coupled with lack of activation in key brain areas of the temporo-parietal-occipital network subtending WMB mechanisms for feature conjunctions. Results detailed in Chapter III reveal that MCI patients’ performance on the WMB task is associated with reduced connectivity of structural networks formed by white matter tracts across the whole brain. Importantly, this held true especially for those MCI patients with more severe WMB deficits. The second aim was addressed in Chapter IV, which reports on crossmodal WMB mechanisms found to be impaired in AD, but not in healthy ageing. This was true regardless of the modality though which features were integrated. Chapter V brings together the relevant findings from Chapter II through IV to review current understanding of WMB as a diagnostic tool for AD. Relevant contributions from the above-mentioned studies are discussed and further research questions generated in the light of current findings. This PhD thesis suggests that WMB functions are disrupted in the course of AD, thus, acknowledging that WMB deficits are a hallmark of the disease since the initial stages of its continuum. As such, WMB tasks are recommended as a valid neuropsychological tool to assess patients cross-sectionally or to screen for patients to be included in intervention trials aimed at investigating long-term effects on the disease progression

The striatum, the hippocampus, and short-term memory binding : volumetric analysis of the subcortical grey matter's role in mild cognitive impairment

Background: Deficits in short-term memory (STM) binding are a distinguishing feature of preclinical stages leading to Alzheimer’s disease (AD). However, the neuroanatomical correlates of conjunctive STM binding are largely unexplored. Here we examine the possible association between the volumes of hippocampi, parahippocampal gyri, and grey matter within the subcortical structures – all found to have foci that seemingly correlate with basic daily living activities in AD patients - with cognitive tests related to conjunctive STM binding. Materials and methods: Hippocampal, thalamic, parahippocampal and corpus striatum volumes were semi-automatically quantified in brain magnetic resonance images from 25 cognitively normal people and 21 patients with Mild Cognitive Impairment (MCI) at high risk of AD progression, who undertook a battery of cognitive tests and the short-term memory binding test. Associations were assessed using linear regression models and group differences were assessed using the Mann-Whitney U test. Results: Hippocampal and parahippocampal gyrus volumes differed between MCI and control groups. Although the grey matter volume in the globus pallidus (r=-0.71, p<0.001) and parahippocampal gyry (r=-0.63, p<0.05) correlated with a STM binding task in the MCI group, only the former remained associated with STM binding deficits in MCI patients, after correcting for age, gender and years of education (β=-0.56,P=0.042) although with borderline significance. Conclusions: Loss of hippocampal volume plays no role in the processing of STM binding. Structures within the basal ganglia, namely the globus pallidus, could be part of the extrahippocampal network supporting binding. Replication of this study in large samples is now needed

Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression

Aims Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. Methods and results All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein–Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. Conclusions Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy